tbuckley/cabot-search huggingface dataset:
Abstract P3012: Syndecan 1 Regulates Lung Endothelial Barrier Function In Homeostatic And Injury Conditions
Authors: Lakshmi Thota, Andreia Chignalia
Journal: Circulation Research (2022)

Introduction: Acute lung injury (ALI) is an inflammatory syndrome that may occur secondarily to bacterial infection. Pulmonary edema is a severe complication of ALI and it may result from endothelial barrier disruption. The mechanisms that initiate ALI during bacterial infection remains unresolved. Syndecan 1 (Sdc1) is a heparan sulfate proteoglycan that contributes to endothelial barrier stability and is cleaved during inflammatory processes. Whether Sdc1 contributes to ALI progression is unresolved. Herein we investigated if Sdc1 mediates LPS-induced ALI in mice. Methods: Male and Female Sdc1 knockout (Sdc1KO) and wild type (WT) mice, with 5-8 weeks of age, were injected with lipopolysaccharide&amp;nbsp;(LPS, 10mg/Kg, IP) or PBS and euthanized after 6hr. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected and assessed for myeloperoxidase (MPO) activity, albumin content, RhoA activity using commercially available spectrometric and ELISA kits. Lung edema was assessed by lung wet/dry ratio (W/D). Results and Conclusions: LPS increased lung W/D by 1.5-fold (p=0.0042, n≥5/group) in WT but not Sdc1KO mice. Sdc1KO showed higher basal lung W/D vs WT (Sdc1KO=3.55 vs WT=2.21, p=0.044, n≥5/group). Similarly, a trend increase in basal lung MPO activity was seen in Sdc1KO when compared to WT (p=0.33, n≥5/group). A significant increase in MPO activity was seen in LPS-treated WT (LPS=0.47±0.03 vs. PBS=0.26±0.03, p=0.003) but not LPS-treated Sdc1KO mice (p=0.11; n≥5/group) when compared to matched PBS-treated strain controls. Albumin content was increased by LPS only in WT BAL (LPS=106.9±8.9 vs PBS=63.65±6.15, p=0.03, n≥5/group). LPS increased RhoA activity exclusively in WT lungs. (LPS=0.04±0.002 vs PBS= 0.02±0.003, p=0.04, n≥5/group). A trend increase in RhoA activity was seen in PBS-treated Sdc1KO when compared to PBS-treated WT (p=0.06, n≥4/group). Collectively, our data suggest that Sdc1KO show basal lung endothelial barrier failure. This phenotype is associated with decreased response to LPS. The mechanisms whereby Sdc1 regulate barrier function may involve RhoA-dependent pathway. Sdc1 may participate in lung edema development during ALI.
Abstract P3065: Myeloid YAP Inhibition Improves Cardiac Phenotype During Pressure Overload Stress
Authors: Jamie J Francisco, Yu Zhang, Yasuki Nakada, Che-Ming Hu, Shinichi Oka, Peiyong Zhai, Dominic Del Re
Journal: Circulation Research (2022)

Inflammation is an integral component of cardiovascular disease and is thought to contribute to cardiac dysfunction in ischemic and non-ischemic models of heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP), a transcription co-factor, in modulating cardiac inflammation in response to ischemic injury; however, whether YAP influences inflammation in the heart during non-ischemic stress is not described. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition in the myeloid compartment is cardioprotective. In mice, PO elicits an immune response characterized by infiltration of myeloid cells that precedes cardiac dysfunction. Myeloid cells isolated from the heart after 7 days PO showed evidence of increased YAP activity. Myeloid-specific YAP knockout mice (YAP F/F ;LysM Cre ) were subjected to PO stress. After 4 weeks cardiac hypertrophy was similar between myeloid YAP KO mice and controls. However, systolic dysfunction, cardiac fibrosis, apoptosis, “fetal gene” induction, and additional indicators of pathological remodeling were attenuated in myeloid YAP KO mice compared to controls. Additionally, inflammatory gene expression and macrophage infiltration in the myocardium were significantly attenuated in myeloid YAP KO mice after PO indicating reduced inflammation compared to controls. Conversely, angiogenic indicators and pro-resolving genes were enhanced in myeloid YAP KO hearts. Experiments using primary bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that YAP suppression attenuated “M1-like” inflammatory gene expression, while “M2-like” resolving genes were augmented following stimulation. The inflammasome is a multiprotein complex and important facilitator of cytokine processing that mediates inflammation in the injured heart. We observed attenuated inflammasome priming and function in YAP deficient BMDMs, as well as in myeloid YAP KO hearts following PO, indicating disruption of inflammasome induction. Finally, we leveraged nanoparticle-mediated delivery of the YAP inhibitor verteporfin to test the translational potential of targeting YAP to prevent heart failure. An alternate-day dosing regimen of drug-loaded nanoparticles attenuated inflammation and fibrosis, and improved myocardial capillary density after PO compared to DMSO nanoparticle control treatment. Together these data implicate myeloid YAP as an important molecular nodal point that facilitates cardiac inflammation and pathology during PO stress and suggest that selective inhibition of YAP may prove a novel therapeutic target in non-ischemic heart disease.
Abstract P1065: Deletion Of Arginine 14 Increases Phospholamban Oligomerization And Disrupts The Cardiac Force-Frequency Relationship
Authors: Sean R Cleary, Taylor A Phillips, Ellen E Cho, Seth L Robia
Journal: Circulation Research (2022)

The Bowditch effect is a physiological phenomenon where accelerated cardiac pacing leads to an increase in the contractile force of the heart. While this has largely been attributed to a frequency-dependent increase in L-type calcium channel influx, evidence suggests intracellular calcium handling proteins must also play an active role. Knock-out of phospholamban (PLB), the inhibitor of the Ca ATPase (SERCA), virtually abolishes the Bowditch effect in mice, suggesting PLB is a major determinant of the cardiac force-frequency relationship. However, no molecular mechanism has explained this frequency-dependent function of PLB. Our lab has previously shown that SERCA loses affinity for PLB when intracellular calcium is elevated. Here, FRET microscopy revealed dynamic decreases in PLB-SERCA binding in response to intracellular calcium elevations. PLB monomers freed from SERCA were rapidly incorporated into PLB pentamers. Interestingly, unbinding of PLB from pentamers was very slow and delayed the recovery of PLB-SERCA complexes by several seconds after calcium elevations. In a computational model of these regulatory binding dynamics, PLB pentamers sequestered inhibitory monomers away from SERCA at fast heart rates. By lowering PLB inhibition of SERCA with increasing cardiac pacing, PLB pentamers serve as a major contributor to the Bowditch effect. Notably, deletion of arginine 14 of PLB causes arrhythmogenic cardiomyopathy and has been thought to destabilize PLB pentamers. Surprisingly, we found R14del-PLB enhanced pentamer stability and slowed the rate of PLB exchange from pentamers to SERCA. We hypothesize that R14del mutation may disrupt frequency-dependent changes in SERCA regulation by PLB during exercise.
Abstract P1106: Loss Of Function Of The Nuclear Envelope Protein LEMD2 Causes DNA Damage-dependent Cardiomyopathy
Authors: Xurde M Caravia, Andres Ramirez-Martinez, Peiheng Gan, John R McAnally, Rhonda Bassel-Duby, Ning Liu, Eric N Olson
Journal: Circulation Research (2022)

Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, which primarily affect the heart and skeletal muscle. A mutation in the NEP LEMD2 causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. As a consequence, there is no specific therapy for this cardiomyopathy. To explore the basis of this pathology, we generated mice carrying the human c.T38&gt;G Lemd2 mutation. These mice represent a new preclinical model that phenocopied the human disease and developed severe dilated cardiomyopathy with extensive cardiac fibrosis leading to premature death. At the cellular level, LEMD2 mutant cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of LEMD2 also died shortly after birth due to heart abnormalities. Both LEMD2 mutant models displayed aberrant cardiac gene expression and extensive DNA damage linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus significantly rescued cardiac function in the c.T38&gt;G mice. Together, our results reveal the essentiality of the nuclear envelope protein LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.
Comparison of bronchial and per oral provocation with aspirin in aspirin-sensitive asthmatics
Authors: B Dahlen, O Zetterstrom
Journal: European Respiratory Journal (1990)

Oral challenge with acetylsalicylic acid was compared with inhalation of Lysine acetylsalicylic acid (L-ASA) as a means to diagnose aspirin-idiosyncrasy in the airways. On the basis of history and/or clinical findings (asthma, rhinorrhea, nasal polyposis) 22 consecutive patients were challenged by both routes. Ten of these developed significant bronchoconstriction (greater than or equal to 20% drop in forced expiratory volume in one second (FEV1)) during either challenge, with the same absolute sensitivity for both tests (9/10). During the bronchial provocations, the reactions developed more promptly (20 min vs 1 h after provocation dose) and were limited to the airways. In contrast, the reactions evoked by the oral provocations were often more pronounced, longer lasting and occurrence of generalized symptoms was more common. Accordingly, the oral tests required more extensive drug treatment for reversal, whereas the bronchial provocations always were reversed by inhalation of bronchodilators. The bronchial method thus resulted in considerably shorter test sessions (4 h vs 8 h). The specificity of the bronchial test was indicated by the observation that a control group of 19 asthmatics with comparable severity of disease failed to bronchoconstrict in response to L-ASA. In conclusion, we have found the bronchial provocation method to be easy to interpret and to control, even in severely asthmatic patients. Consequently, bronchial provocation with L-ASA appears particularly useful in the out-patient office or for research on airway responses to ASA in ASA-sensitive asthmatics.
Abstract P2047: Identification Of Selective Small-molecule ERBB4 Agonists With Cardioprotective Effects
Authors: Eline Feyen, Julie Cools, Jens Van fraeyenhove, Michiel Tubeeckx, Hans De Winter, Dominique Audenaert, Tine Bruyns, Gilles De Keulenaer, Vincent Segers
Journal: Circulation Research (2022)

Introduction: Morbidity and mortality of heart failure remain high, mandating new therapeutic approaches. The neuregulin-1 (NRG1)/ERBB4 axis is cardioprotective and an attractive target for treatment. Clinical trials with recombinant NRG1 are ongoing, but require intravenous administration, limiting applicability and efficacy. Purpose: To develop selective small-molecule ERBB4 agonists with cardioprotective effects. Methods: A high-throughput screening of 10,240 compounds (cpds) was performed on a ERBB4/ERBB4 dimerization assay. Hit cpds were co-administered with NRG1 or fluorescently labeled NRG1 to determine competitive binding. Selectivity, receptor phosphorylation, toxicity and metabolic stability were determined using Luminex RTK phosphoprotein, ERBB2/ERBB3 dimerization and adenylate kinase assays or LC-MS/MS. Apoptotic and hypertrophic effects of cpds (4-32μM) on cultured cardiomyocytes were studied after exposure to 100μM H 2 O 2 and 100nM angiotensin II (AngII). Antifibrotic effects (4-32μM) were studied on TGF-β-induced collagen synthesis in cultured human fibroblasts, and in mice (n=9-10/group) treated with AngII (1000 ng/kg/min) or cpd (83 μg/kg/h) using osmotic pumps. Results: We identified 8 similar pyrimidine derivatives inducing ERBB4/ERBB4 dimerization (Emax 9-33% relative to NRG1, EC50 6E-6 to 2E-7M). Competition assays indicated allosteric receptor binding and potentiation of NRG1-induced ERBB4 receptor dimerization, up to 2.7 fold (P&lt;0.0001). Six were non-toxic and induced ERBB4 phosphorylation, but ERBB1, ERBB2 or ERBB3 phosphorylation remained unaffected and cpds did not induce ERBB2/ERBB3 dimerization, showing ERBB4 selectivity. Cpds showed a t1/2 of 170min in human liver microsomes. Cpds attenuated hypertrophic and apoptotic effects of AngII or H 2 O 2 (P&lt;0.05), and decreased collagen upregulation in vitro (P&lt;0.05). In vivo , a selected cpd attenuated AngII-induced myocardial interstitial fibrosis (-76±26%, P&lt;0.01), and cardiac Col1a1, Col3a1 (-64±22%; -71±25%, P&lt;0.01) and Nppa (-77±22%, P&lt;0.01) mRNA expression. Conclusion: We identified selective novel pyrimidine derivative small-molecule ERBB4 agonists with cardioprotective effects in vitro and in vivo .
Familial spontaneous pneumothorax
Authors: P Lenler-Petersen, N Grunnet, TW Jespersen, P Jaeger
Journal: European Respiratory Journal (1990)

In a three generation family with 27 members we examined a relationship could be found between spontaneous pneumothorax and HLA-haplotypes, alpha 1-antitrypsin phenotypes or concentration or lung volumes and ventilatory capacity. Eight individuals in the family suffered from spontaneous pneumothorax. No relationship with the investigated markers could be found in this informative family. All patients showed normal lung volumes and ventilatory capacity after recovery.
Abstract P1028: The Epicardium As The Conductor Of Cardiovascular Cells In Cardiac Regeneration
Authors: Patrick H Rericha, Maria T Colzani, Laure Gambardella, Vincent Knight-Schrijver, Semih Bayraktar, Johannes Bargehr, Robyn Macrae, Jonathan Lee, Scott Dillon, Sanjay Sinha
Journal: Circulation Research (2022)

Regenerative cardiovascular medicine is emerging as a promising therapeutic alternative to heart transplantation in patients suffering from chronic heart failure. Although promising, challenges to cell therapy for cardiac repair remain, including cell survival, maturation, graft size, revascularisation, and immunogenicity. It has recently been shown that co-transplantation of human embryonic stem cell (hESC)-derived epicardial cells (EPI) with hESC-derived cardiomyocytes (CM) improves cardiac repair processes with respect to engraftment, cell maturation, and graft and host vascularisation. One plausible explanation for the observed benefits of co-transplantation is paracrine-mediated effects. While RNA sequencing data has been used to identify putative players in hESC-EPIs, little is known about their involvement in mediating hESC-CM maturation and revascularization, in particular in communication with endothelial cells (EC). Here, the role of paracrine signalling in hESC-EPI-mediated promotion of hESC-CM maturation and angiogenesis is being investigated with an emphasis on the involvement of extracellular vesicles (EVs). hESC-EPI-EVs improved responsiveness to pacing and coordination of contraction in vitro in hESC-CM cell culture and engineered heart tissues (EHTs). Moreover, hESC-EPI-EVs and hESC-EPI supernatant excluding EVs independently promoted tube formation in in vitro gel-based angiogenesis assays. hESC-EPI supernatant excluding EVs also promoted EC proliferation in MTS assays and EC migration in wound closure assays. Characterisation of the hESC-EPI-EV-cargo on a protein level revealed candidate factors involved in cardiac repair processes. Together with hESC-EPI-EV miRNA-sequencing and hESC-EPI gene expression data key paracrine signalling pathways and candidate factors to manipulate them are being identified and investigated in in vitro angiogenesis and CM maturation assays. Promising angiogenesis promoting candidates are being validated in vivo using yolk-sac membrane and chorioallantoic membrane assays. Identification of the paracrine signalling pathways involved would make it possible to effectively address selected cardiac repair processes, resulting in new approaches to therapy.
Abstract P3060: Circulating Gut Microbial Peptides Exacerbate Cardiac Dysfunction In IL10KO Mice Following Transaortic Constriction
Authors: Prabhat Ranjan, Sumanta Goswami, Roshan Kumar Dutta, Ram Prasad, qinkun zhang, Hind Lal, Suresh Verma
Journal: Circulation Research (2022)

Background: Heart failure is the leading cause of morbidity and mortality in the USA. Recently, impaired intestinal permeability is known to augment cardiac dysfunction. Though, the cardioprotective role of IL10 is well known, its role in reducing gut dysbiosis and maintaining intestinal permeability during hypertrophic heart failure is not known. We hypothesized that IL10 maintains intestinal permeability and inhibits the release of gut microbial peptides (GMPs) which ultimately improves cardiac function. Methods: WT &amp; IL10KO mice were subjected to TAC or sham surgery. Heart and intestine were collected to evaluate inflammation genes expression, immune cell infiltration (flow cytometry), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify peptidoglycan (PGN) and other bacterial metabolites (TMAO) levels. The effect of PGN on mitochondrial functions was evaluated in neonatal cardiomyocytes. Results: Cardiac functions were significantly reduced in IL10KO mice following TAC. IL10 KO mice showed exacerbated inflammation (IL1β, IL6 and TNFα genes expression) following TAC. TAC induced leukocytes (monocyte/macrophage, T-cell and neutrophils) recruitments in the intestine in IL10KO mice. TAC mice showed gut dysbiosis (16S rRNA sequencing) in IL10KO mice. Further, IL10KO mice exhibited higher intestinal permeability as shown by increase in PV1 level and reduction in zonulin-1 (ZO-1) protein. Plasma PGN level was significantly increased in IL10KO mice following TAC. Pathway-based cardiotoxicity array showed a significant increase in uncoupler protein 2 (UCP2) and phospholamban (PLN; a calcium handling protein) genes expression in cardiomyocytes following PGN treatment. Finally, IL10 treatment restores PGN-induced decrease in mitochondrial membrane potential (TMRE assay) in cardiomyocytes. Conclusion: Taken together, data suggest that IL-10 helps to maintain gut wall permeability and reduced gut microbial peptide circulation to the heart and thus improves cardiac function by improving mitochondrial function. Ongoing investigations using molecular approaches will provide a better understanding of gut-heart signaling and its impact on the progress of heart failure.
Pleural tuberculosis
Authors: J Ferrer
Journal: European Respiratory Journal (1997)

Tuberculous pleural effusions occur in up to 30% of patients with tuberculosis. It appears that the percentage of patients with pleural effusion is comparable in human immunodeficiency virus (HIV)-positive and HIV-negative individuals, although there is some evidence that HIV-positive patients with CD4+ counts &lt;200 cells x mL(-1) are less likely to have a tuberculous pleural effusion. There has recently been a considerable amount of research dealing with the immunology of tuberculous pleurisy. At present, we have more evidence that activated cells produce cytokines in a complex pleural response to mycobacteria. Intramacrophage elimination of mycobacterial antigens, granuloma formation, direct neutralization of mycobacteria and fibrosis are the main facets of this reaction. With respect to diagnosis, adenosine deaminase and interferon gamma in pleural fluid have proved to be useful tests. Detection of mycobacterial deoxyribonucleic acid (DNA) by the polymerase chain reaction is an interesting test, but its usefulness in the diagnosis of tuberculous pleurisy needs further confirmation. The recommended treatment for tuberculous pleurisy is a 6 month regimen of isoniazid and rifampicin, with the addition of pyrazinamide in the first 2 months. HIV patients may require a longer treatment. The general use of corticosteroids is not recommended at this time, but they can be used in individuals who are markedly symptomatic.
Abstract P3140: Targeting Of Kinin B1r/il-6 Signaling Prevents Microvascular Leakage And Mitochondrial Dysfunction In Sepsis Induced Heart Failure
Authors: Kaichao Pan, Qin Zhang, Karim Ullah, Ani Solanki, Allbert Sitikov, James K Liao, Rongxue Wu
Journal: Circulation Research (2022)

Introduction: Cardiovascular dysfunction is a major complication of severe sepsis. Microvascular leakage and mitochondrial dysfunction during sepsis are critically involved in heart failure. However, the underlying mechanisms between cardiac microvascular barrier function and sepsis-induced heart failure are not well studied. Kinin B1 receptor (B1R) regulates inflammation and induces capillary leakage. Previous findings from our lab also revealed an increase in B1R serum level in both septic patients and animal models within 24 hours. Hypothesis: We hypothesized that treatment with B1R antagonist protects against sepsis-induced microvascular leakage and mitochondrial dysfunction. Methods and Results: To address the hypothesis, we pre-treated WT male mice with either vehicle (control) or a specific B1R antagonist B6929 via subcutaneous injection, then subjected them to 40% cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Echocardiographic analysis revealed an early cardioprotective effect of B1R inhibition, as evidenced by the improvement of EF%, FS%, and cardiac output in mice pre-treated with B1R antagonist (n=6-8, p&lt;0.01) at 4-6 hours post-CLP. Furthermore, mitochondrial H 2 O 2 measurement of the freshly isolated cardiac mitochondria from CLP-induced septic mice also showed that B1R inhibition partially abolished the production of H 2 O 2 . The opening of mPTP was also reduced with B1R antagonist treatment. In vivo cardiac vascular permeability assessed using the Miles assay further demonstrated that B1R inhibition prevented sepsis-induced cardiac microvascular leakage and edema. Similar improvements were also observed in the liver and kidney. Interestingly,B1R antagonist treatment abolished CLP-induced serum level of IL-6 by 70%. In in-vitro study, B1R antagonist treatment inhibited LPS-induced IL-6 expressions in human cardiac microvacuolar endothelial cells (HCMECs). Finally, ECIS based analysis demonstrated that IL-6 deletion using either siRNA or B1R antagonist treatment rescued LPS-induced endothelial barrier leakage. Conclusions: Our findings suggest that targeting B1R via IL-6 may be a novel therapeutic approach for the treatment of sepsis-associated cardiovascular disease.